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The following message was posted to: PharmPK
Dear all,
I am trying to convince people that a K-PD model could be developed, without
having actual PK data. Does anyone have a reference that clarifies the meaning
of a K-PD model? And shows that indeed, actual PK data are not fully required?
Thank you
Best regards
Hester
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Hi,
This KPD method has been used in several ways (See Holford & Peace 1992, Jacqmin et al
2007). Note that the Jacqumin method uses the rate of entry of drug into the effect
compartment as the driving force for pharmacological effect which is not consistent with
standard pharmacological theory. Standard theory proposes that effects are driven by drug
concentration not rate of delivery.
Nick
Holford NH, Peace KE. Methodologic aspects of a population pharmacodynamic model for
cognitive effects in Alzheimer patients treated with tacrine. Proc Natl Acad Sci U S A
1992; 89: 11466-70.
Jacqmin P, Snoeck E, van Schaick EA, Gieschke R, Pillai P, Steimer JL, Girard P. Modelling
response time profiles in the absence of drug concentrations: definition and performance
evaluation of the K-PD model. J Pharmacokinet Pharmacodyn 2007; 34: 57-85.
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The following message was posted to: PharmPK
Dear Nick,
Although I agree that it is commonly assumed that concentration, rather than rate, is driving effect, Paton proposed an alternative theory supporting the latter (http://rspb.royalsocietypublishing.org/content/154/954/21.short). Admittedly, this work never made it into main-stream pharmacology, however, it does raise its head every now and then when we are trying to explain 'unexpected findings'. In particular, it may be the case that different molecular targets (GPCRs, ion channels, kinase receptors etc.) adhere to different laws and one could even speculate that different physiological systems use one or the other or both principles as control mechanisms. Advances in systems pharmacology will no doubt shed more light on these matters.
Best,
Piet
Piet van der Graaf
CPT:Pharmacometrics & Systems Pharmacology
www.nature.com/psp
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The following message was posted to: PharmPK
Hi Piet
Interesting article. Out of interest - what findings can be explained by the
rate of drug-receptor combination that cannot be explained by receptor
occupancy?
I can understand that using rate may help you to investigate rapid tolerance
phenomena but these can also be explained by receptor occupancy models.
Regards
Steve
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The following message was posted to: PharmPK
Hi Steve,
The main area where Paton's model (or different rate models such as serial
binding and productive hit rate models) has been applied is in studies of
pharmacological efficacy. Differential potency (EC50) can easily be explained
by occupancy models but intrinsic activity (Emax) cannot, i.e. why does one
ligand behave as an agonist and another (which binds equally well to the
receptor) not. Rate theory suggests that this is not determined by the number
of occupied
receptors but by the rate of receptor occupation. This would also provide an
alternative framework for understanding rapid tolerance development.
Not widely accepted, but as you can see at
http://rspb.royalsocietypublishing.org/content/154/954/21.short there are some
recent papers in very respectable journals citing the original paper. I am not
aware however of any application of the model in the context of PKPD.
Best,
Piet
Piet van der Graaf
CPT:Pharmacometrics & Systems Pharmacology
www.nature.com/psp
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Piet,
Thanks for reminding me of the Paton 'rate' model. But this is quite different
from the Jacqmin KPD model. Paton proposed that the effect is proportional to
the rate of binding to the receptor site. Jacqmins model does not involve the
rate of receptor binding but rather the nominal 'infusion rate' of drug to the
effect compartment where the effect is mediated.
There is really no difference between the Paton rate model and the occupancy
model because the rate of binding at equilibrium is proportional to the
occupancy (see p24 above eqn 2 in Paton's paper). Thus the models are
essentially indistinguishable if the dissociation rate constant remains
unchanged.
Nick
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